Heartburn, or pyrosis, is a sensation of pain or burning located substernally or high in the epigastrium with radiation into the neck and occasionally to the arms, associated with regurgitation of acid-peptic gastric juice into the esophagus. Occassional heartburn is common in normal persons, but frequent and severe heartburn is generally a manifestation of esophageal dysfunction. Heartburn may result from abnormal motor activity or distention of the esophagus relfux of acid or bile into the esophagus, or direct esophageal mucosa irritation (esophagitis).
Heartburn is most often associated with gastroesophageal reflux. In this setting, heartburn typically occurs after a meal, with stooping or bending, or when the patient is supine. It may be accompanied by the spontaneous appearance in the mouth of fluid which may be salty, sour, or bitter and green or yellow. Heartburn may arise following the ingestion of certain foods (e.g. citrus fruit juices) or drugs (e.g. alcohol or aspirin). Characteristically, heartburn is alleviated promptly, even if only temporarily, by antacids.
Heartburn may also occur in the absence of a demonstrated anatomic or physiologic condition. In this setting, it is frequently accompanied by aerophagia, which may represent an attempt by the patient to relieve discomfort, and is often attributed to psychological factors for lack of other explanations.
Reflux esophagitis consists of esophageal mucosal damage resulting from reflux of gastric or intestinal contents into the esophagus. Esophagitis, an inflammation of the esophagus from regurgitation of acid gastric contents, producing substernal pain, develops when the mucosal defenses that normally counteract the effect of injurious agents on the esophageal mucosa succumb to the onslaught of the refluxed acid pepsin or bile. Mild esophagitis shows microscopic changes of mucosal infiltration with granulocytes or eosinophils, hyperplasia of basal cells, and elongation of dermal pegs. Erosive esophagitis shows endoscopically visible damage to the mucosa in the form of marked redness, friability, bleeding, superficial linear ulcers, and exudates.
Famotidine (available from Merck & Co., Inc., Whitehouse Station, N.J., under the name PEPCID.RTM.), is an antagonist of the histamine H.sub.2 receptor, is 3-{{{2-[(aminoiminomethyl) amino]-4-thiazolyl]methyl]thio]-N-(aminosulfonyl)propanimidamide, having the structural formula: ##STR1## The primary clinically important pharmacologic activity of famotidine is inhibition of gastric secretion. Both acid concentration and volume of gastric secretion are reduced by famotidine. Famotidine is used to treat acid-related disorders such as gastric and duodenal ulcer, gastroesophageal reflux disease and Zollinger Ellison syndrome. Its safety and efficacy have been well established in controlled clinical studies, and use by over 31 million patients worldwide.
Studies of oral administration have shown that the onset of antisecretary effect occurs within one hour, and that the maximum effect, occurring within 1 to 3 hours, was dose dependent.
Single evening doses of 20 and 40 mg were shown to inhibit mean nocturnal gastric secretion by 86% and 94% respectively, for a period of 10 hours. The same doses, given in the morning, suppressed food stimulated acid secretion by 76% and 84%, respectively, 3 to 5 hours after administration, and 25% and 30%, respectively, 8 to 10 hours after administration. In some subjects who received 20 mg dose, the antisecretory effect was dissipated within 6 to 8 hours.
Trials have shown famotidine to be beneficial in a dose dependent manner in relief of symptoms associated with ulcerations and gastritis.
Gitlin et al., Amer. Journal of Gastroenterology (1985) vol. 80 pp. 840 examines famotidine efficacy in the treatment of active duodenal ulcers. The results suggest that duodenal ulcer healing rates are famotidine dosage dependent. 20 mg twice daily, 40 mg twice daily and 40 mg at bedtime were administered over a four week period. Healing rates of 67, 75, 70%, respectively, were seen.
Similarly, Miyoshi et al., Naika Hokan (1987) vol. 34 pp. 442-457 demonstrates that the efficacy of famotidine as a gastritis therapy is dose-related. Miyoshi et al. evaluated dosage regimens of 5, 10, or 20 mg twice daily in the treatment of gastritis symptom relief. Patients treated with 10 to 20 mg of famotidine had fewer erosions and mucosal haemorrhages than those treated with 5 mg famotidine.
McCallum et al., Dig. Dis. Sci. (1985) vol. 30 pp. 1139-1144 describes a study of healthy patients demonstrating that 5 mg of famotidine produces has an effect on gastric acid secretion. Laskin et al., J. Clin. Pharmacol. (1993) vol. 33 pp. 636-639 describes a study demonstrating that single doses of 5 and 10 mg of famotidine produces statistically significant decreases in intragastric acidity, beginning at 90-100 minutes and persisting for approximately 9 hours. Neither study measured the effects of 5 mg or 10 mg doses of famotidine on patients having pyrosis without esophagitis or pyrsosis with esophagitis.
Applicants have now administered doses of 5 mg, 10 mg, and 20 mg to patients suffering from heartburn without esophagitis (showing no substantial esophageal erosion), and to patients suffering from heartburn with esophagitis (showing substantial esophageal erosion). Applicants have found that the success in treating patients suffering from heartburn without esophagitis is not dose dependent, i.e., the benefit achieved by administering a 5 mg dose of famotidine to patients suffering from heartburn without esophagitis is substantially the same as the benefit achieved by administering a 10 mg dose, and that the benefit achieved by administering a 10 mg dose of famotidine to patients suffering from heartburn without esophagitis is substantially the same as the benefit achieved by administering a 20 mg dose of famotidine.